Nrf3在血管平滑肌细胞分化和表型转换及血管损伤新生内膜形成中的作用及机制研究

Vascular smooth muscle cells (VSMCs) are important and vulnerable cells in vascular diseases such as atherosclerosis, post-angioplasty restenosis, and aneurysm et.al. Both stem/progenitor cell differentiation and VSMC phenotypic modulation participate in vascular remodeling. Our previous work suggested that Nrf3 may play a key role in vascular system. We found that Nrf3 inhibited adventitial adult stem/progenitor cell differentiation to VSMCs, and promoted mature VSMCs phenotypic switching to proliferative and migratory state. Moreover, in vascular injury induced neointma formation, Nrf3 expression was dramatically increased. In addition, we created Nrf3-/- knockout mice and found that Nrf3 depletion attenuated injury-induced neointimal hyperplasis. Therefore, we hypothesize that Nrf3 can regulate vascular remodeling through affecting stem/progenitor differentiation and modulating VSMCs functions. In this project, we will try to discover the exact role of Nrf3 in adventitial stem/progenitor differentiation, as well as its function in VSMCs proliferation, migration, apoptosis and inflammatory cytokine secretion. Additionally, the underlying mechanism will be extensively studied. This project can help to fully understand the pathogenesis of injury-induced neointima formation and develop a potential new theraputic target.

血管平滑肌细胞(VSMCs)在血管稳态破坏中极易受累、功能异常，是心血管系统疾病如动脉粥样硬化(AS)、血管介入术后再狭窄、动脉瘤等的关键细胞。干祖细胞分化VSMCs和VSMCs的表型转化共同参与血管重构。本项目组的前期工作发现Nrf3在心血管系统中可能发挥重要作用，并且在预实验结果中，我们发现Nrf3抑制血管外膜成体干/祖细胞分化为成熟VSMCs；同时Nrf3促进VSMCs增殖和迁移功能；此外在血管损伤内膜增生过程中，Nrf3表达显著升高；最后我们构建了Nrf3-/-转基因小鼠，发现Nrf功能缺失能明显减轻内膜病理性增生。因此，本项目拟从VSMCs的来路和去路两方面，研究Nrf3对成体干/祖细胞分化为成熟VSMCs的影响和对VSMCs增殖、迁移、凋亡、炎性因子分泌等功能的影响，揭示Nrf3在VSMCs和损伤诱导的内膜新生中实际作用和具体分子机制，为发展新的血管疾病治疗靶点提供思路。

Nrf3 是近年来发现的具有高度保守碱性亮氨酸拉链结构域的 cap’N’collar family（CNC）转录因子家族成员。已有研究认为：Nrf3 可作为转录因子启动基因的转录翻译，调控分子表达，并与细胞的氧化应激相关。项目组的前期工作发现Nrf3抑制血管外膜成体干/祖细胞分化为成熟血管平滑肌细胞。在本项目中进一步研究了Nrf3在成熟血管平滑肌细胞功能调控和血管损伤病理性重构中的作用。通过构建Nrf3缺失小鼠及平滑肌细胞特异性Nrf3敲除小鼠，结合血管平滑肌细胞体外表型转化模型，首次揭示了Nrf3通过与下游靶分子Trim5的启动子区域结合，促进Trim5的表达，进而通过Trim5介导的自噬调控血管平滑肌细胞表型转化，促进血管平滑肌细胞的增殖、迁移及炎症反应，最终促进血管损伤后新生内膜形成。本项目揭示了Nrf3在血管平滑肌细胞和损伤诱导的内膜新生中实际作用和具体分子机制，为发展新的血管疾病治疗靶点提供思路。